Multimodal treatment according to the NPC‐GPOH trials in adult patients with nasopharyngeal cancer—Analysis based on a single‐center experience

Abstract Background and Aim The German NPC‐GPOH trials introduced treatment including neoadjuvant chemotherapy, radiochemotherapy (RCT) and antiviral treatment in patients aged 25 years or younger with nasopharyngeal cancer (NPC). We conducted a retrospective study on outcomes of patients at the age of ≥26 years treated accordingly at our institution. Methods Consecutive patients who received primary RCT for NPC were included. The Kaplan–Meier method was used to calculate survival probabilities, and the Cox regression analysis was used to test for an influence of the variables on outcomes. Acute and late toxicity were evaluated via CTCAE criteria and LENT/SOMA criteria, respectively. Results In total, 30 patients were included. Diagnosis was made from 09/1994 to 11/2016. The median 5 year overall survival (OS), disease‐free survival (DFS), cancer‐specific survival (CSS) and locoregional recurrence‐free survival (LRC) were 75%, 56%, 83%, and 85%, respectively. We found a negative impact on outcomes (p < .05) in case of older age (OS), history of smoking (OS), and T4 stage/ UICC stage IV (DFS). WHO histologic type significantly influenced outcomes, with best outcomes for type III and worst outcomes for type I. The rates of acute and late toxicities were acceptable. Conclusion We found excellent outcomes and good feasibility of the NPC‐GPOH trials regimen in adult patients. Additionally, we identified patients with outcomes which need to be improved (smokers, histologic type I tumors) and with particularly excellent outcomes (histologic type III tumors). This stimulates further studies on treatment intensification or de‐escalation aiming at reduced side effects with optimal tumor control in NPC.

Nasopharyngeal cancer (NPC) rarely occurs in Western Europe. 1 There are distinct differences between NPC in childhood or adolescence and NPC in adulthood: adults present with a less advanced stage at diagnosis and, paradoxically, have a worse prognosis. 2,3The World Health Organization (WHO) classification comprises keratinizing squamous cell carcinoma (type I) and nonkeratinizing carcinoma, which includes differentiated (type II) and undifferentiated carcinoma (type III). 4 A high percentage of nonkeratinizing carcinomas are Epstein-Barr virus (EBV)-associated.Both nonkeratinizing type and the presence of EBV are positive prognostic factors. 5,6][9][10][11] Recognizing the distinct features of the EBV-associated carcinomas, the NPC-91-GPOH trial and, subsequently, the NPC-2003-GPOH/DCOG trial, included adjuvant antiviral treatment with interferon-β (IFN-β) after RCT in children and adolescents.The authors reported excellent outcomes and an acceptable toxicity profile. 7,12,13sed on the results, we started to treat all patients in accordance with these protocols.With respect to aforementioned known differences between NPC in childhood or adolescence and adulthood, it is worth investigating whether this regimen can achieve similar results in adults.Therefore, we analyzed outcomes of NPC patients at the age of 26 years or older who were consecutively treated at our institution.
Results of a subgroup of this patient cohort were previously published by Wolff et al. with special focus on type III tumors and IFN-β treatment. 14In this study, we report outcomes with an updated and extended patient cohort and analyze the influence of patient-and treatment-related variables.

| Patients
We included patients who were treated with primary RCT for NPC of WHO type I-III (description of subtypes in accordance with the 1991 WHO classification 4,15 ) at the age of 26 years or older.Patients were excluded in case of distant metastases.Patients were staged with upper endoscopy, tumor biopsy (including testing for the presence of EBV according to local standards), computed tomography scan of the head and neck region, and assessment of lung and liver (either using a chest radiograph and ultrasound examination or computed tomography).This investigation was approved by the local ethics committee of the University of Göttingen Medical Center (application number 9/6/19).It was conducted in accordance with the Declaration of Helsinki principles.

| RCT and immunotherapy
Radiation therapy was delivered to the primary tumor and to the bilateral neck.Patients were immobilized using a customized thermoplastic mask.Treatment techniques were: 2D planning from 1994 to 1999, 3D planning from 1999 to 2008, and intensity modulated radiotherapy from 2008 (details of planning techniques were described before by Wolff et al. 16 ).Based on the respective trials, concomitant chemotherapy was applied starting in the 1990s, while induction chemotherapy was used first in 2003, based on the results of the NPC-91-GPOH trial. 7,12,17The NPC-91-GPOH trial used an induction chemotherapy with 3 cycles of methotrexate, cisplatin, and 5-fluorouracil, followed by radiotherapy up to a total dose of 59.4 Gy. 12 The subsequent NPC-2003-GPOH/DCOG 2012 trial (in cases of UICC stages III-IV) included an induction chemotherapy with 3 cycles of cisplatin, 5-fluorouracil, and folinic acid, followed by RCT (with concomitant cisplatin [20 mg/m 2 /d on 3 consecutive days, during the first and last week of irradiation]) up to a total dose of 59.4 Gy (in cases of complete remission after induction chemotherapy: 54 Gy). 7In both studies, adjuvant IFN-β (10 5 IU/kg, 3 days per week) was applied for a period of 6 months. 7,12cording to local practice, in case of medical contraindications, chemotherapy was omitted.After RCT, adjuvant immunotherapy was given in patients with WHO type I and II tumors only in case of positivity for EBV and in patients with WHO type III tumors.The decision for IFN-β application was made on an individual basis by an interdisciplinary team of the University of Göttingen Medical Center.Patients received thorough information and were informed about the individual character of the treatment before giving informed consent.

| Follow-up and toxicity
During RCT, patients were examined weekly.Acute toxicity was assessed using CTCAE criteria. 18The medical records were evaluated.
Toxicities were clinically judged according to the current CTCAE classification v5.0. 19After RCT, follow-up was conducted in cooperation with the local department of otorhinolaryngology.Regular follow-up examinations included upper airway endoscopy and computed tomography scans of the head and neck.Intervals were left at the discretion of the treating radiation oncologist or otorhinolaryngologist.Late toxicity was evaluated using the LENT/SOMA criteria. 20

| Statistics
The survival times were calculated starting from the day of histopathological diagnosis.For the respective definitions see Birgisson et al.
(here defined for case of colorectal cancer). 21Locoregional control (LRC) was defined as the time to recurrence of primary tumor or recurrence in cervical lymph nodes.Disease-free survival (DFS) was defined as the time to locoregional recurrence, distant metastases, second primary cancer, or death from any cause.Cancer-specific survival (CSS) was defined as the time to death from NPC. CSS events only included deaths specifically caused by NPC progression.Deaths due to other causes (e.g., unknown cause, deaths from toxicities) were censored at that time.The Kaplan-Meier method was used to calculate survival rates.The Cox regression analysis was used to test for an influence of the variables on outcomes, using a cut-off value of p < .05.Due to the small sample size, we decided for bivariate categorization of cT stage and AJCC stage.Jen et al. proposed a grouping system for NPC which integrated cT stage and AJCC stage by means of recursive partitioning analysis. 22Here, cT4 stage resulted in assignment to the most unfavorable group. 22Additionally, AJCC stage IV was associated with considerably lower survival (5 year overall survival (OS), 73.7%) when compared to stages I-III (5-year OS, 89.2%-94.0%). 22Thus, as a pragmatic approach for the presented study, the categorization (cT1-3 vs. cT4 and AJCC stages IV vs. other stages) was used for survival analysis.Data were analyzed using the software STATISTICA (v13.3,TIBCO Software Inc.) and SPSS Statistics (v26, IBM).The survival curves were drawn using the software R (version 4.3.3)with the plugin KMWin (version 1.53).

| Patients and treatment
We screened 42 patients who were treated for NPC in our clinic.In total, 30 patients were included for further analysis (see Figure S1).
Diagnosis was made between 09/1994 and 11/2016.The median follow-up was 52.0 months (range, 1.9-103.8).For details of patient and treatment characteristics, see Tables 1 and S1

| Outcome
The median 5 year OS, DFS, CSS, and LRC rates were 75%, 56%, 83%, and 85%, respectively (See Figures 1 and S2-S4).There were three events of locoregional recurrences: one patient experienced local recurrence and two patients experienced cervical lymph node recurrences.Distant metastases occurred in six patients.A total of 11 patients died during follow-up.Among them, five patients died due to NPC.The remaining causes of death were unknown.In three patients, second primary tumors occurred during follow-up (basalioma, breast cancer, and leukemia).
We found a negative impact on outcomes ( p < .05) in case of older age (OS), history of smoking (OS), and T4 stage/ UICC stage IV T A B L E 1 Baseline patient and disease characteristics.(DFS).Furthermore, WHO histologic type significantly influenced outcomes, with best outcomes for type III and worst outcomes for type I (DFS, OS; Table 2).

| Toxicity
In the whole patient cohort, 16 patients experienced high-grade (≥grade 3) acute organ toxicity.Eight patients experienced relevant late toxicity (≥grade 2).See Tables 3 and 4 for further details.Three patients had a feeding tube prior to RCT.Additionally, during the course of treatment, 11 patients received a feeding tube.The reasons for incomplete application of the different treatment modalities (percentages of patients: see Table 1) were: fever and adverse gastrointestinal effects (IFN-β application incomplete, n = 1), systemic progression under RCT (radiotherapy and concomitant chemotherapy incomplete, n = 1), by patient request due to grade 1 mucositis (radiotherapy incomplete, n = 1), and acute kidney injury (chemotherapy incomplete, n = 1).

| DISCUSSION
Recent trials established a sequence of induction chemotherapy, RCT and IFN-β application as a highly effective treatment for NPC in children and adolescents. 3,7,12,13Accordingly, we introduced this treatment regimen into our clinic for adults.The incidence of NPC has a bimodal age distribution. 3Since the aforementioned studies excluded patients in the second peak of NPC incidence (fifth decade 3 ), there is less known about treatment results in this patient group.Thus, in this study we present an updated analysis of this special patient cohort treated in our clinic.Especially since most of the patients were diagnosed in advanced tumor stages, our 5 year OS and CSS rates of 75% and 83%, respectively, represent excellent outcomes.These are comparable with previous reports from our institution and from the German study group. 7,12,14 further improve outcomes, recently, the specific components and sequences of multimodal treatment have been intensively studied and discussed. 11,23The concomitant chemotherapy is very well established. 11Accordingly, it was given to the vast majority of patients (90%) in our study.During follow-up, distant metastases occurred in a relevant percentage of patients (20%), which can be compared with the rates reported in current literature. 11Additionally, we found a negative influence of advanced tumor stages on outcomes.Both findings emphasize the need for a further treatment optimization or an escalation of systemic treatment.The induction chemotherapy represents a possible approach.5][26][27] In our study, approximately half of the patients received this additional treatment.However, we could not demonstrate a clear benefit of an induction chemotherapy, possibly due to the small sample size.
As a further approach to improve treatment results, the German NPC-GPOH trials started to treat adolescent patients with IFN-β in 1992.As Wolff et al. reported in 2010 for parts of the presented cohort treated in our clinic, 14 the integration of IFN-β into multimodal treatment strategy yields excellent results and does not relevantly affect treatment tolerability.Now, we additionally tested for an influence of IFN-β application on outcomes, and, however, firm conclusions cannot be drawn due to the small sample size.To our knowledge, probably due to the rarity of the disease, further comparable data about antiviral treatment in NPC are very rare. 7,12,14,28In general, treatment approaches which address different components of the immune system gained relevant interest and should be studied in the near future. 3,29Furthermore, it is known that histologic type is a relevant prognostic factor in NPC. 6,30The NPC-GPOH trials included patients with WHO type II and III tumors and reported outcomes for the whole patient cohort, irrespective of histological type. 7,12Other previous studies reported a poor prognosis for WHO type I tumors. 6,30This could be confirmed in our study.So far, in case of comparison of type II and type III tumors, a consistent prognostic difference could not be demonstrated. 6,31In our study, we found that patients with type III tumors had a significantly better prognosis than patients with type I-II tumors.It is known that type III tumors are more closely associated with an EBV infection. 2,12Additionally, there is evidence that this implies both an enhanced sensitivity to RCT and to antiviral treatment. 32,33Thus, the biological tumor characteristics might plausibly explain the favorable prognosis of type III tumors.
Interestingly, considering virus-associated carcinomas, a similarly favorable prognosis is known for human papillomavirus-associated oropharyngeal cancers. 34This highlights the special characteristics of these tumors in the head and neck region and points out to the need to develop particular strategies for therapeutic management.In case of NPC, these strategies could include the use of pre-treatment EBV viral load, which was demonstrated to be a useful prognosticator, 35 and the use of EBV viral load after primary RCT for follow-up or to guide adjuvant treatment. 36In our study, firm conclusions cannot be drawn concerning the effect of IFN-β on outcomes, putatively due to the retrospective design and small sample size.Previous studies demonstrated that patients with high EBV viral load are at increased risk of recurrence and death. 36Thus, the need for adjuvant treatment (e.g., with IFN-β) might be high in this patient group.However, further studies are required to test this hypothesis.
Additionally, we found that patient age and smoking status were significant outcome predictors.8][39][40] The negative impact of patient age might be attributed to more comorbidities and therefore to an increased risk of death from other causes than NPC. 39Smoking can foster the occurrence or deterioration of various diseases, promote tumor growth, and reduce the efficacy of RCT. 37,38Unfortunately, since the cause of death is unknown for a relevant proportion of our patients (6 out of 11 patients), it is difficult to draw further conclusions from our study.However, as reported by previous studies, our results indicate that elderly patients and smokers require special attention, possibly owing to reduced treatment efficacy and increased risk of side effects. 41,42 our study, 53% of patients experienced relevant (≥III ) acute toxicity.The acute toxicity rates can be compared to recent studies. 7 terms of patient quality of life, late toxicity is more relevant. 43In our study, 27% of patients experienced relevant (≥II ) late toxicity.
In particular, xerostomia (23% of patients, III in 2 patients) was an important side effect, in accordance with previous reports. 44There were no cases of other possible severe side effects (e.g., temporal lobe necrosis with neurologic symptoms), possibly due to the high percentage of patients (67%) with modern IMRT or VMAT irradiation techniques. 44,45Additionally, the rates of incomplete treatment The presented study has limitations which have to be mentioned.GPOH trials are beneficial in adult patients.Lastly, the lack of patientreported quality of life (beyond physician-reported side effects) is a shortcoming of our study. 43,46However, since the vast majority of NPC cases occur in the endemic regions of Asia and Africa, reports on treatment results throughout Europe are very rare (e.g., in Germany: Roeder et al. 47 and Saleh-Ebrahimi et al. 48).3][14] Thus, overall, our study's results add relevant new findings to a poorly studied subject of research.

| CONCLUSIONS
In adult patients, we found excellent outcomes and good feasibility of the NPC-GPOH trials regimen.Additionally, we found evidence for patient subgroups with a special need to improve outcomes (smokers, WHO type I tumors) and with particularly excellent outcomes (WHO type III tumors).This stimulates further studies on treatment intensification or de-escalation aiming at reduced side effects with optimal tumor control in NPC.As a suggestion, future studies could reduce treatment intensity (e.g., radiotherapy dose reduction) in patients with WHO type III tumors.An intensified treatment (e.g., systemic treatment) seems reasonable in patients with WHO type I tumors.In the light of recent studies, the EBV viral load at diagnosis and/or after RCT could serve as a valuable tool for tailored treatment (e.g., patient selection for adjuvant IFN-β application).Additionally, further recently introduced immunotherapeutics 49 could improve treatment outcomes.

Firstly, in a
retrospective study with a small number of patients, the treatment was performed during a long time period which implies different lengths of follow-up, and different irradiation techniques.Second, patient selection for each component of multimodal treatment (e.g., induction chemotherapy and adjuvant IFN-β application) was carried out nonrandomized by different physicians, based on individual patient characteristics according to respective treatment patterns.These factors represent biases for the study results.Consequently, firm conclusions concerning the influence of the induction chemotherapy or the IFN-β application on outcomes cannot be drawn.Additionally, since only one patient received the radiotherapy dose of 54 Gy after complete response to induction chemotherapy, we cannot draw further conclusions on oncologic outcomes with reduced radiotherapy dose in NPC patients.Thus, we are not able to clarify whether these specific components of the pediatric protocol of the NPC- Influence of baseline patient, disease, and treatment characteristics on outcomes.
F I G U R E 1 Overall survival for the whole patient cohort.T A B L E 2Note: The results of the univariable Cox regression analysis are given (hazard ratios and 95% confidence intervals).We used a cut-off value of p < .05.Abbreviations: CSS, cancer-specific survival; DFS, disease-free survival; IFN-β, interferon-β; LRC, locoregional control; OS, overall survival.a AJCC, 7th ed.b 1991 WHO classification.